CZ292229B6 - Process for preparing amides of alpha-(N,N-dialkyl)-aminocarboxylic acids - Google Patents

Abstract

The present invention relates to a process for preparing {alpha}-(N,N-dialkylamino)-carboxamides of the general formula I, in which the symbols Re1 through Ri5 have specific meanings. The novel preparation process is characterized by bringing into reaction corresponding free acids with primary or secondary amines in the presence of alkanephosphonic acid anhydrides, whereby amino acid or peptide derivatives are used as the primary or secondary amines.

Description

A process for the preparation of .alpha .- (N, N-dialkyl) -amino carboxylic acid amides

Technical field

The present invention relates to a process for the preparation of .alpha .- (N, N-dialkyl) aminocarboxylic acid amides. It relates to a process for the non-racemic reaction of α- (N, N-dialkyl) amino acids with amines to form carboxylic acid amides.

BACKGROUND OF THE INVENTION

Many natural substances which exhibit interesting pharmacological effects and active substances structurally derived therefrom are α- (N, N-dialkyl) amino acids of the general formula Π

R ¹

AND

N - CH - CO - OH

They are of interest as building units (for example enkephalin: U. Schmit et al., Liebigs Ann. Chem. 1985, 1254-1261, dolastatin: G. R. Pettit et al., Tetrahedron 49 (41) 9151-9170, WO93 / 23424). For example, from Ν, Ν-dimethylvaline (Ha) and the tetrapeptide, the antineoplastic drug dolastatin 10 is obtained.

tetrapeptide

Ha

The coupling of (N, N-dialkyl) amino acids (IIa) with the speptides is difficult, in the case of dolastatin 10 the yield was only 53% (J.Poncet et al. Tetrahedron 50, 5345-5360 (1994)). This poor outcome, where a significant portion of valuable tetrapeptides are lost in dolastatin synthesis, is not according to U. Schmidt et al. (Liebigs Ann. 1985, 1254-1262) not surprising.

U. Schmidt also studied the association of Ν, Ν, -dimethylamino acids in connection with the synthesis of enkephalins. Only three methods have been shown to be useful for activating these amino acids:

1. Activation of Ν, Ν-dimethylamino acids by conversion to pentafluorophenyl ester:

-1 CZ 292229 B6

This method is used, for example, by G. R. Pettit et al. (J. Am. Chem. Soc. 1991,113 (6992-6993) for the synthesis of dolastatin 15. Pentafluorophenol, a fairly expensive reagent which is not available in sufficient quantities for technical syntheses, is used as the starting compound for this multi-step process. the use leads, inter alia, to the formation of fluorine-containing waste, which can be removed only very difficultly and probably to produce dioxins.

2. As an alternative, U. Schmidt recommends activation with 3-cyano-4,6-dimethyl-2-pyridinthiol:

O

However, cyanopyridine is not commercially available and must be obtained in a multi-step process.

3. A third alternative is to activate the dimethylamino acid with diethylphosphonicanidan (= DEPC) (GR Pettit, Tetrahedron 1994 50 (42,12 097-12 108). Also, this reagent is not commercially available in the quantity required for technical synthesis Therefore, a multi-step additional process is necessary: highly toxic solutions containing cyanide should be used in the production and conversion of DEPC.

There is therefore an urgent need for processes that allow for the simple coupling of N, N-dimethylamino acids.

There is interest not only in coupling peptides with Ν, Ν-dimethylamino acids, but also in peptide bonds with Nbenzyl-N-methylamino acids. The residual benzyl serves as a protecting group which can be removed by hydrogenolysis.

Although N-benzyl-N-methylamino acids are relatively easy to obtain as peptide building blocks, they are very rarely used, since there are no useful methods for the non-racemation linkage of these amino acids.

Thus, exclusively N-acyl-N-methylamino acids (Acyl-butoxycarbonyl (BOC), benzyloxycarbonyl (Z), which are more difficult to obtain than N-benzyl), are used to obtain peptides composed partly of N-methylamino acids (e.g. cyclosporins, dolastatins). The N-methylamino acids, however, exhibit substantially less racemization tendency when coupled (example: dolestatin 15-synthesis according to GR Pettit, J. Am. Chem. Soc. 1991 113 6692-6693).

A suitable binder would also be required for the use of N-benzyl-N-methylamino acids.

This coupling of carboxylic acid with amines in the presence of alkanephosphonic anhydrides and their conversion to amides is an easy to use process (EP 156834) which can also be used to obtain peptides (EP 156280). The propanephosphonic acid n-anhydride (PPA) is preferably used. However, the usefulness of this reagent has been demonstrated only for N-acylamino acids not alkylated on nitrogen.

A variety of suitable binding agents are available for such reactions. The applicability of alkanephosphonic anhydrides for the coupling of the Ν, dial-dialkylamino acids of formula I has not yet been verified.

In view of the above, it has therefore been some surprise that alkanephosphonic anhydrides are suitable binding agents for coupling α- (N, N-dialkyl) amino acids.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of the α- (N, N-dialkylamino) carboxamides of formula (I)

Rl

I **

N - CH - CO - N

RS (I) in which

R ¹ is C ^ alkyl, _C3 _7 cycloalkyl, phenyl, benzyl, (CH _{2) 3} NH (C = NH) NH _2, CH ₂ CONH ₂ CH ₂ CO ₂ H, CH ₂ SH, (CH ₂₎ CONH ₂ , (CH ₂ ) ₂ CO ₂ H, imidazolyl-5-methylene, (CH ₂ ) ₄ NH ₂ , (CH ₂ ) ₂ SCH ₃ , CH ₂ OH, CH (OH) CH ₃ or indolyl-3- methylene, the reactive groups being protected as necessary with protective groups,

R ² represents a C] _6 alkyl, or benzyl which is optionally substituted by Ci-4-alkyl, C ^ alkoxy, nitro, CF _3, chloro, fluoro or bromo,

^R3 is Ci_6-alkyl or benzyl which is optionally substituted C ^ -alkyl, C _M alkoxy, nitro, CF _3, chloro, fluoro or bromo, where R ¹ and R ² may be joined together,

R ⁴ and R ⁵ are each independently hydrogen, C 1-6 -alkyl, C 1-7 -cycloalkyl, phenyl, which may be substituted with 1, 2 or 3 fluorine, chlorine or bromine atoms or C 1-5 -alkyl, C 1-6 alkoxy or CF ₃ , an aromatic heterocycle which may be substituted with 1, 2 or 3 fluorine, chlorine or bromine atoms or C 1-6 -alkyl, C 1-6 -alkoxy or CF ₃ or benzyl which may be substituted with 1, 2 or 3 fluorine, chlorine or bromine atoms or C 1-5 -alkyl, C 1-6 -alkoxy or CF ₃ , wherein R ⁴ and R ⁵ may optionally be joined together and where NR ⁴ R ⁵ may also be an amino acid residue or a peptide residue, the carboxyl group and other functional groups being protected by protecting groups, wherein the corresponding free acids of formula Π are reacted

R ¹

AND

N-ch-CO-OH (II)

R 6 with primary or secondary amines of the formula ^{R 6}

HN, R5 in the presence of alkanephosphonic anhydrides.

In particular, primary or secondary amines may be mentioned as follows:

^ R ⁴

H -— N

R ⁵

- amines such as ammonia, methylamine, ethylamine, propylamine, butylamine, isobutylamine, benzylamine, cyclohexylamine, dimethylamine, diethylamine, benzylmethylamine, dibenzylamine, pyrrolidine, hydroxy and methylpyrrolidine, piperidine, hydroxy- and methylpiperidine, piperidine, piperidine, piperidine, piperidine, piperidine, piperidine N-methylaniline, morpholine, alkylmorpholine, aminopyridine

- amino acid derivatives such as alanine ester and amides, N-methylalanine, glycine, N-methylglycine, isoleucine, N-methylisoleucine, methionine, N-methylmethionine, phenylglycine, N-methylphenylglycine, phenylalanine, N-methylphenylalanine, proline, tryptophan, N-methyltryptophan, valine,

N-methylvaline, β-alanine, N-methyl-β-alanine

- peptides, such as Val-MeVal-OMe MeVal-Val-OMe, Val-OMe, Val-NH _2, Val-NHBz, Val-Val-MeVal-Pro-OMe, Val-MeVal-Val-Pro -NH ₂ , Val-MeVal, Val-Pro-

NHBz, Val-MeVal-Val-Pro-NHiProp, Val-MeVal-Pro-ProNH ₂ , Val-MeVal-Pro-ProNHBz, Val-MeVal-Pro-Pro-NHiProp.

When R ^{1 is a} C 1-6 -alkyl- or C 3-7 -cycloalkyl group, there are in particular: methyl, isopropyl, isobutyl, 1-methyl-n-propyl-1-yl, cyclopropyl and cyclohexyl.

C 1-6 -alkyl groups specifically mentioned for R ¹ are also preferred for R ² , R ³ , R ⁴ and R ⁵ . As cycloalkyl groups, mention may be made of R ⁴ and R ⁵ . Cycloalkyl groups for R ⁴ and R ^{5 are, in} particular, cyclopropyl and cyclohexyl.

Suitable aromatic heterocycles for R ⁴ and R ^{5 are} preferably residual thiazole, thiophene and pyridine.

R ⁴ and R ⁵ may also be bridged together so that R ⁴ R ⁵ are then available for (CH ₂ ) ₄ , (CH ₂ ) ₅ , CH ₂ CH ₂ OCH ₂ CH ₂ , (CH ₂ ) ₆ .

R ¹ and R ³ may be linked to each other. C 1 -C ₄ -alkyl-substituted pyrrolidines and piperidines are optionally formed.

In addition to the alkyl group, R ² may also be optionally substituted residual benzyl. C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, nitro, CF ₃ , Cl, F, Br are suitable as substituents.

Thus, the process of the present invention is suitable both for obtaining N, N-dialkylamino acids amides I, and particularly for obtaining peptides.

The reaction is carried out at temperatures from -10 ° C to +40 ° C. Preferably, temperatures ranging from -5 ° C to room temperature. Suitable reagents are straight or branched chain alkanephosphonic anhydrides or cyclic alkanephosphonic acids having a chain length of 1 to 8 carbon atoms, preferably propanephosphonic anhydride (PPA). Other examples include methanephosphonic anhydride, ethanephosphonic acid 45 and butanephosphonic anhydride.

The alkanephosphonic anhydride may be recovered in a manner known per se, for example as described in Houben-Weyl, Emth. d. Org. Chem. (1963), vol. ΧΠ / 1, p.

-4GB 292229 B6

In obtaining the peptides, it is expedient to work with particularly pure alkali phosphonic anhydrides. Such anhydrides are obtained by reacting pure alkanephosphonic acid dichlorides with 1 mole of water followed by removal of residual hydrogen chloride in vacuo.

Preferably, the process described in German Patent Application No. 2,811,628 is used to obtain these anhydrides.

In this process, pure alkanephosphonic acid is converted to the anhydrides by thermal cleavage of water. Subsequent purification by vacuum distillation may be expedient. The reaction is preferably carried out in a neutral or weakly alkaline environment.

For the condensation reaction, a buffered medium obtained by adding aliphatic and cycloaliphatic tertiary bases, such as N-methylmorpholine, N-ethylmorpholine, trialkylamines with up to 6 C-atoms per residual alkyl, is expediently selected. Triethylamine and diisopropylethylamine have proven particularly useful in this regard. Suitable solvents are dimethylsulfoxide, DMF, DMA, N-methylpyrrolidone, chloroform, methylene chloride, THF, dioxane and methyl acetate.

In addition to the N-N-dialkylamino acid, resp. N-benzyl-N-alkylamino acids and alkanephosphonic anhydrides amino acid or carboxyl-blocked peptide. All protecting groups customary in peptidosynthesis can be used to protect this carboxyl group.

The alkanephosphonic anhydrides are preferably used in excess (2 to 2.5 moles of alkanephosphonic anhydrides per mole of amode binder).

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Me ₂ Val-Val-MeVal-Pro-Pro-NHBz x HCl

To a solution of 8.7 g of LN, N-dimethylvaline, 27.4 g of Val-MeVal-Pro-Pro-NHBz x HCl and 21.6 g of triethylamine in 100 ml of CH ₂ Cl ₂ was added dropwise over 20 minutes 42.4 g. 50% solution of propanephosphonic acid n-anhydride in ethyl acetate at 0 to 65 ° C. The solution was stirred for 1 hour in the cold and at room temperature overnight. The organic phase was washed and concentrated with 50 ml of water. The residue was diluted in 50 mL of isopropanol and acidified with 10 mL of 30% isopropanol HCl. After seeding, 150 ml of methyl tert-butylene was added at 60 ° C, stirred overnight, then aspirated, washed with isopropanol and dried. 29.9 g (88.3%) of Me ₂ Val-Val-MeVal-Pro-Pro-NHBz x HCl were obtained. HPLC purity - area percentage: 99.8% (no epimer not detectable).

Example 2

Me ₂ Val-Val-MeVal-Pro-Pro-NHBz x HCl

To a solution of 21.6 g of dimethylvaline, 54.8 g of Val-MeVal-Pro-Pro-NHBz x HCl and 54 g of diisopropolethylamine in 100 ml of CH ₂ Cl ₂ was added dropwise 84.8 g of a 50% n-acid anhydride solution over 45 minutes. propanephosphonic acid in ethyl acetate at -75 ° C. The whole was stirred for 1 hour in the cold and at room temperature overnight. The organic phase was washed and concentrated with 200 mL of saturated NaCl solution and 100 mL of 10% NaOH. The residue was dissolved in 350 mL of 2-butanol. 25 ml of a saturated isopropanol solution was added

-5GB 292229 B6

HCl and 200 ml MTBE, stirred overnight, then aspirated and dried in vacuo. 61.4 g (90.5%) of the product was obtained, HPLC purity - area percentage: 99.8% (no epimer not detectable).

Example 3

To a solution of 50 g of N-benzyl-N-methylvaline in CH 2 Cl 2 was added 120 g of diisopropylethylamine. At -55 to 5 ° C, 37.7 g of proline methyl ester hydrochloride and 176.8 g of a 50% solution of propanephosphonic anhydride in ethyl acetate were added. Everything was stirred for 1 hour in the cold and at room temperature overnight. The organic phase was washed with 400 ml of water, 200 ml of 1 N NaOH and twice with water, dried over Na2SO4 and concentrated. 49.6 g (65.4%) of the product was obtained, HPLC purity - area percentage: 93.7%. The content of other diastereomers was less than 1%.

Example 4

To a solution of 6.5 g of N-benzyl-N-methyl-valine and 16.3 g of diisopropylethylamine in methylene chloride was added 9.9 g of Pro-pro-NHBz x HCl and 24.3 g at -55 ° C to 5 ° C. of a 50% solution of n-propanephosphonic anhydride in ethyl acetate. After stirring for 1 hour in the cold and at room temperature overnight, the organic phase was washed with water, 1 N NaOH and water, dried over Na 2 SO 4 and concentrated. 14.4 g (93.4%) of HPLC purity remained: area percentage: 96.1%. The content of other diastereomers was less than 1%.

Claims (5)

PATENT CLAIMS A process for the preparation of α- (N, N-dialkylamino) carboxamides of the general formula I R ^l I ^R ' N CH - CO - N R 3 - R ⁵ (D, in which ^R1 is Ci_6-alkyl, _C3 _7 cycloalkyl, phenyl, benzyl, (CH _{2) 3} NH (C = NH) NH _2, CH ₂ CONH ₂ CH ₂ CO ₂ H, CH ₂ SH, (CH ₂₎ CONH _2j (CH ₂ ) ₂ CO ₂ H, imidazolyl-5-methylene, (CH ₂ ) ₄ NH ₂ , (CH ₂ ) ₂ SCH ₃ , CH ₂ OH, CH (OH) CH ₃ or indolyl-p-methylene, wherein the reactive the groups are protected by protective groups as appropriate, R ² is C ^ -alkyl or benzyl which is optionally substituted C-alkyl, Cl 4 alkoxy, nitro, CF _3, chloro, fluoro or bromo, R ³ represents C 1-6 -alkyl or benzyl which is optionally substituted with C 1-6 -alkyl, C 1-6 -alkoxy, nitro, CF ₃ , chloro, fluoro or bromo, where R ¹ and R ² may be joined together, R ⁴ and R ⁵ are independently hydrogen, Ci_e alkyl, _C3 _7 cycloalkyl, phenyl which may be substituted with 1, 2 or 3 fluorine, chlorine or bromine atom or Ci_5-alkyl, Ci_s-alkoxy or CF ₃ an aromatic heterocycle which may be substituted by 1, 2 or 3 fluorine, chlorine or bromine atoms or a C 1-5 -alkyl, C 1-5 -alkoxy or CF ₃ group or benzyl which may be substituted by 1, 2 or 3 fluorine, chlorine or bromine atoms or C 1-6 alkyl, C 1-5 -alkoxy or CF ₃ , wherein R ⁴ and R ⁵ may optionally be joined together and wherein NR ⁴ R ⁵ may also be an amino acid residue or a peptide residue, the carboxyl group and other functional groups being protected by protecting groups, characterized in that the corresponding free acids of the formula Π are reacted AND N — CH — CO --OH (II), wherein R ¹³ is as defined above, with primary or secondary amines of formula HN ·> _R 5 wherein R ⁴ and R ⁵ are as defined above in the presence of alkanephosphonic anhydrides. The method according to claim 1, characterized in that amino or peptide derivatives are used as primary or secondary amines. Process according to claim 1, characterized in that n-propanephosphonic anhydride is used as the phosphonic alkane anhydride. Process according to claim 1, characterized in that a, Ν-dimethyl- and N-benzyl-N-methylaminocarboxylic acids are used as α-dialkylaminocarboxic acids. ίο The process according to claim 1, characterized in that N, N-dimethylvaline, Ν, Ν-dimethylisoleucine, N-benzyl-N-methylvaline or N-benzyl-N-methylisoleucine are used as α-dialkylaminocarboxic acid.